Patent application title: Methods and Formulations for the Efficient Delivery of Drugs by Nebulizer

Abstract:

Formulations, methods and devices for producing formulations and methods
for nebulizer delivery of formulations of water-insoluble drugs and drugs
requiring storage in aqueous or other water-miscible pharmaceutically
unacceptable vehicles for stability are provided. Also provided are
methods for minimizing wastage of drugs administered by nebulizer, and
for the achievement of quantitative dosing with diluent from a mass
marketed formulations, which because of the mass market is much less
costly per dose than formulations manufactured specifically for much
lower volume medical use.

Claims:

1. A method for delivery of a drug via a nebulizer to a patient
comprising:(a) dissolving a drug in a small volume of a pharmaceutically
unacceptable vehicle for shelf life storage separate from diluent with
which it is intended to be nebulized;(b) mixing the drug solution with a
large volume of pharmaceutically acceptable aqueous media prior to
nebulization, said large volume of aqueous media being large enough to
operate the nebulizer and said resulting mixture being pharmaceutically
acceptable for nebulization;(c) adding the resulting mixture to a
nebulizer; and(d) delivering said resulting mixture to the patient via
the nebulizer.

2. The method of claim 1 wherein the large volume of aqueous media
comprises a water-soluble drug to be administered concurrently with the
drug dissolved in the pharmaceutically unacceptable vehicle.

3. The method of claim 1 wherein the pharmaceutically unacceptable vehicle
in which the drug is dissolved is an aqueous solution.

4. The method of claim 3 wherein the pharmaceutically unacceptable vehicle
is an aqueous solution having a high pH or a low pH as compared to
physiological pH.

Description:

[0001]This patent application is a continuation of U.S. application Ser.
No. 11/353,591, filed Feb. 14, 2006, which is a continuation-in-part of
U.S. application Ser. No. 10/168,120, filed Oct. 7, 2002, issued as U.S.
Pat. No. 7,029,656, which is the U.S. National Stage of PCT Application
No. PCT/US00/34304, filed Dec. 15, 2000, which claims the benefit of
priority from U.S. Provisional Application Ser. No. 60/171,997, filed
Dec. 23, 1999, teachings of each of which are herein incorporated by
reference in their entireties.

BACKGROUND OF THE INVENTION

[0002]Asthma is a chronic inflammatory disorder of the airways in which
inflammation contributes to hyper responsiveness to allergic and irritant
stimuli, to airflow limitation, to a broad spectrum of respiratory
symptoms, and to disease chronicity. Features of this inflammatory
process include denudation of airway epithelium, edema, recruitment and
activation of various types of migratory inflammatory cells, and
increased basement membrane collagen deposition which is believed to be
the cause of the chronic changes known as asthmatic airway remodeling.

[0003]Topically acting corticosteroids are the most potent and
consistently effective long-term control medication for asthma. Their
broad action on the inflammatory process may account for their efficacy
as preventive therapy. Their clinical effects include reduction in
severity of symptoms, improvement in peak expiratory flow rate and
spirometry, diminished hyper responsiveness of airways, prevention of
exacerbations, and possibly the prevention of airway wall remodeling.
Further, there are data suggesting that earlier treatment with inhaled
topically acting steroids, measured in years following diagnosis of
asthma, results in better long term outcome and lower cumulative
aggregate dose of steroids needed for optimal control.

[0004]Topically acting corticosteroids for asthma are generally
administered as aerosolized droplets released into a spacer or holding
chamber from a pressurized metered dose inhaler, and slowly inhaled from
expiration or resting lung volume to maximum inspiratory volume by the
patient, who then holds his breath for at least 10 seconds. Alternative
devices are dry powder inhalers, activated by sucking from expiration or
resting lung volume to maximal inspiration, followed by similar
breath-holding.

[0005]The most widely favored delivery system for inhaled asthma
medications for children who are too young to effectively use metered
dose aerosols or dry powders, and for patients of any age whose airways
are so irritable that they will cough out medications inhaled from
metered dose or dry powder inhalers, up to the present time, has been the
compressor-driven jet nebulizer. This device generates a mist of droplets
of medication in aqueous solution which is inhaled through either a
mouthpiece or a mask. Greater precision and efficiency in target tissue
delivery, greater portability and greater user convenience are driving
the device market for administration of newer inhaled drugs toward
microporous membrane nebulizers, in which a piezoelectric oscillator
directly or indirectly vibrates a thin metal or ceramic membrane adjacent
to the fluid to be nebulized, causing cavitation at the sites of numerous
uniformly sized pores in the plate which drives the fluid through the
pores in droplets that are very uniform in size. Both types of nebulizer
are designed to efficiently nebulize liquids with the nebulization
characteristics or physiologic characteristics approximating those of
physiologic saline. Jet nebulizers designed for individual patient use
generally have a dead space of ˜1 ml and require working volumes of
2-5 ml for efficient operation. Commercially available microporous
membrane nebulizers have no dead space and drugs to be used with them are
generally formulated in dose volumes of 0.25 to 2 ml.

[0006]Topically acting corticosteroids are not sufficiently water-soluble
to deliver effective treatment doses in practical volumes of aqueous
nebulizer solution. Many of these drugs are sufficiently soluble in
non-aqueous solvents that unit doses could be packaged in solvent volumes
that are below the threshold of toxicity, but these volumes are below the
threshold for accurate and effective delivery by either jet or
microporous membrane nebulizers.

[0007]There have been previous attempts to overcome this problem.

[0008]Metered dose aerosol holding chambers have been designed with valves
and masks, to be placed over a child's mouth and nose, so that droplets
of medication sprayed into the chamber from an "adult" metered dose
asthma inhaler will be inhaled in the course of either the child's normal
breathing, or (as many young children resist the devices) the child's
crying. Some parents, some physicians and some investigators find these
devices convenient and effective, many find them much less so.

[0009]Unit doses of small, easily aerosolized particles of
water-insoluble, topically-acting steroids have been packaged with
aqueous vehicles for nebulizer administration as aqueous suspensions.
Such products have shelf life stability problems because of agglomeration
of small drug particles into larger ones over time.

[0010]The recently published international PCT application WO 99/44594
discloses a drug delivery system in which water-insoluble drugs are
prepared as lipid-water emulsions, freeze-dried, and dispersed in water
for nebulization. Emulsions, like suspensions, are two-phase systems
which, over time, undergo physical transition to lower energy states.
Maintenance of a boundary between phases takes energy, so that a lower
energy state can be achieved by reducing the surface area of this
boundary. For a solid-in-liquid suspension the physical transition that
takes place over time is particle agglomeration. For an emulsion, it is
dissociation.

[0011]The present invention is an application of a model based on
principles of physical chemistry, for the design of formulations of
topically acting corticosteroids and other water-insoluble drugs for
nebulizer inhalation in aqueous vehicles, which avoid the problems of
particle agglomeration and dissociation of emulsions. The present
invention also allows the economy of multiple dose packaging of
concentrated drug in a state that is both ready-to-use and physically
stable.

SUMMARY OF THE INVENTION

[0012]An object of the present invention is to provide formulations and
procedures for preparing formulations using commercially marketed sterile
saline, sterile buffered saline or other sterile aqueous diluents, as
vehicles for the nebulizer delivery of water-insoluble drugs and drugs
requiring storage in non-physiologically acceptable aqueous vehicles. In
the present invention, a water-insoluble drug is dissolved in a
non-aqueous solvent at a sufficiently high concentration that the volume
of non-aqueous solvent per dose of drug is non-toxic. Alternatively, a
water-soluble drug with poor chemical stability and/or limited shelf-life
in physiologically acceptable aqueous vehicles is dissolved in a
non-physiologically acceptable vehicle at a sufficiently high
concentration that the volume of non-physiologically acceptable vehicle
per dose of drug is either non-toxic by itself or can be rendered
non-toxic by mixing with a nebulizable volume of an appropriately
formulated diluent. In these embodiments, treatment doses in measured
small volumes of these non-aqueous or non-physiologically acceptable
aqueous solutions can be mixed, immediately prior to nebulization, with
larger volumes of aqueous vehicles formulated to render them
physiologically acceptable. This results in formulations of sufficient
volume to be administered effectively via commercially available
nebulizers. For drugs in a non-aqueous solution, these formulations
exhibit characteristics of a two-phase liquid-liquid suspension.
Dispersion of a small volume of the discontinuous, non-aqueous phase is
maintained by the mixing action of the nebulizer in a large volume of
continuous aqueous phase for the 10-20 minutes needed for administration
of the treatment dose. For drugs in an aqueous non-physiologically
acceptable solution, physiologic compatibility is restored prior to
dosing by the mixing action of the nebulizer with a large volume of a
physiologically acceptable aqueous vehicle for the 10-20 minutes needed
for administration of the treatment dose. The large volume of aqueous
phase added to produce the nebulizer formulation may also contain
additional water-soluble drugs to be delivered to a patient concurrently
with the water-insoluble drug dissolved in the non-aqueous phase of the
suspension.

[0013]Another object of the present invention is to provide a method for
improving delivery efficiency of any drug, water soluble or not,
administered via non-continuous-flow jet nebulizer or ultrasonic
nebulizer technology. This method involves "washing into the patient"
with an extra aliquot of sterile diluent, most of the average of 40% of
each dose left in present-day jet and certain ultrasonic nebulizers when
the volume remaining in the device drops below the threshold needed for
effective mist generation. This is done when the nebulizer stops
generating mist, by adding additional sterile aqueous diluent to the
nebulizer chamber, without additional drugs, restarting the nebulizer,
and having the patient inhale the resulting aerosol until mist generation
stops, again.

[0014]Another object of the present invention is to provide a device for
quantitative measurement and dosing of sterile diluents such as buffered
sterile saline from pressurized multi-dose, non-metered-dose canisters.

[0015]Yet another object of the present invention is to provide a device
for clean, accurate and inexpensive measurement and dosing of small
volumes of drugs in concentrated solution from multi-dose bottles.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016]FIGS. 1a, 1b, and 1c show an embodiment of a measuring device for
quantitative measurement and dosing of sterile diluents in preparation of
formulations of the present invention. In this embodiment, the support of
the device comprises two pieces, a trapezoidal rest, to support the tube
at a selected angle and a triangular brace which provides structural
support for the rest. FIG. 1a provides a side view diagram of the tubular
body in its resting position in the support. FIG. 1b provides an end-view
diagram of the measuring device in the same position. FIG. 1c provides a
bottom view of this device.

[0017]FIGS. 2a, 2b, and 2c show another embodiment of a measuring device
for quantitative measurement and dosing of sterile diluents in
preparation of formulations of the present invention. In this embodiment,
the support of the device comprises two triangular wings upon which the
tubular body rests and a trapezoidal bridge located between the wings for
support. FIG. 2a provides a side view diagram of the tubular body in its
resting position in the support. FIG. 2b provides an end-view diagram of
the measuring device in the same position. FIG. 2c provides a view from
the bottom, perpendicular to the long excess of the tubular portion of
the device.

[0018]FIG. 3 provides a cross-sectional side view of a device to
facilitate measuring and dosing small volumes, i.e. 0.05 to 0.5 ml, of
non-water-soluble drugs from a multi-dose bottle for nebulizer
formulation in a clean, inexpensive and accurate manner.

DETAILED DESCRIPTION OF THE INVENTION

[0019]Water-insoluble drugs, such as topically acting asthma
corticosteroids, are often sufficiently soluble in non-aqueous solvents
such as, but not limited to, various glycols and/or alcohols alone or in
combination, so that therapeutic doses can be in non-toxic solvent
volumes of 0.05 to 0.5 ml. Such solutions are physically stable (i.e.,
they do not dissociate or agglomerate over the shelf life of the product)
and they can be packaged inexpensively in multi-dose containers. They
cannot be administered in this form with presently available nebulizers,
however, because non-toxic volumes of their non-aqueous vehicles are
insufficient for the operation of currently available nebulizers.

[0020]The present invention relates to new formulations comprising
water-insoluble drugs and methods of delivering these formulations via
nebulizer. In the present invention, single doses of water-insoluble
drugs dissolved in small volumes of non-aqueous solution are mixed with
larger volumes of aqueous vehicles just prior to nebulization. The
aqueous vehicle may also contain water-soluble drugs to be administered
concurrently with the water-insoluble drug. Accordingly, multiple
prescribed inhaled medications can often be administered together using
the formulations described herein.

[0021]What results is a formulation comprising a safe, small volume of
non-aqueous vehicle containing water-insoluble drug, suspended in a
sufficiently large volume of aqueous vehicle for effective delivery with
proven, presently available nebulizer technology. While the exact
molecular structure of the resulting mixture has not been determined, the
physical behavior and/or characteristics of the mixture are that of a
two-phase liquid-liquid suspension. By "nebulizer technology" it is meant
to include both reliable and inexpensive jet nebulizers that are widely
used at this time for delivery by inhalation of water-soluble drugs to
infants and children with asthma, and improvements of the same or
functionally comparable technologies such as ultrasonic nebulizers, to
increase efficiency, alter drug deposition within the respiratory tract
by varying particle size, and/or reduce treatment time.

[0022]The same principles of physical chemistry govern boundary behavior
of all two-phase systems. Previously developed formulations for nebulizer
administration of water-insoluble drugs in aqueous media involve the
generation of a suspension prior to packaging. All such formulations will
slowly dissociate and/or agglomerate during storage without the input of
additional energy to maintain dispersion. With the present invention,
however, a different outcome is achieved because of differences in both
the timing of dispersion and the energy required to achieve and maintain
dispersion.

[0023]In the present invention, the aqueous and non-aqueous components of
the formulation are stored separately as stable one-phase solutions, and
mixed immediately prior to nebulization. The energy required to achieve
dispersion is sufficiently low when both aqueous and non-aqueous phases
are low viscosity liquids, as in the formulations of the present
invention, that dispersion can be created and maintained for what is
usually a 10 to 20 minute duration of treatment, by the mixing action of
the nebulizer used for administration of the drug.

[0024]It takes energy to maintain the boundary between the phases of a
two-phase suspension. In the absence of an external source of this
energy, every random molecular movement that reduces the total surface
area of boundary between the two phases, will slightly disaggregate it,
as the energy released by the reaction is dissipated into the environment
as heat, and unavailable to energize molecular movement in the opposite
direction. Accumulation of these spontaneous molecular movements over
time results in particle agglomeration in solid particle suspensions, and
in disaggregation of emulsions. Disaggregation does not occur with the
formulation of the present invention because the aqueous and non-aqueous
components are not mixed until the time of nebulization, and the energy
needed to both create and maintain dispersion is provided by the
operation of the nebulizer.

[0025]Examples of topically acting steroids for which this invention now
makes possible the development of stable preparations for nebulizer use
include, but are not limited to, beclomethasone, budesonide, flunisolide,
fluticasone, mometasone and triamcinolone.

[0026]For the purposes of this invention, by "safe" it is meant a volume
of non-aqueous solvent which is sufficiently small in quantity to pose
either no significant risk of toxic effects, or a smaller risk of toxic
effects than the alternative treatments the same patients would need in
the absence of treatment using the present invention. As will be obvious
to those of skill in the art upon this disclosure, the upper volume limit
of "safe" may be different for different solvents and for infants and
children of different ages. For any specific new drug application, the
sponsor would have to satisfy the F.D.A. (or, for use in other countries,
the appropriate regulatory office or administration) that the proposed
volumes of the individual proposed solvent are in fact safe.

[0027]By "small" volume of non-aqueous solvent, it is meant a volume small
enough not to perturb the nebulization characteristics of the mixture in
comparison to the nebulization characteristics of the continuous aqueous
phase if nebulized alone. "Small" is any volume that would become the
discontinuous phase of what in the formulations of the present invention
behaves as a two-phase liquid-liquid suspension which nebulizes with
approximately the surface tension, droplet size, mist generation rate and
other physical properties of the continuous, aqueous phase.

[0028]By "large" volume of aqueous phase, it is meant a volume large
enough to operate the nebulizer. The device that is provided when a
physician prescribes a compressor-driven nebulizer or a compressor-driven
jet nebulizer for asthma, usually operates efficiently with a fill volume
of up to 4 ml of a liquid with nebulization characteristics of
physiologic saline. It stops generating mist, depending upon the model,
when the body remaining in the chamber drops below 0.5 to 1.0 ml.
Accordingly, for most such nebulizers, by large volume it is meant from
about 2.5 to about 4 ml. Smaller operating volumes leave an unacceptably
high percent of content in the chamber at the end of mist generation.
Volumes much larger than about 4 ml do not allow enough room in presently
available nebulizer chambers for effective mist generation. Since the
physical properties of the aqueous phase are major determinants of the
surface tension, droplet size, mist generation rate and other physical
properties of formulations that behave as two-phase, liquid-liquid
suspensions, the volume of this phase can be adjusted within the 2.5 to 4
ml range to optimize these properties.

[0029]The economy of packaging water insoluble-drugs as concentrated
solutions in multi-dose containers is practical for the overwhelming
majority of nebulizer applications, as the delivery systems in which they
are used must be clean but not sterile. The equipment, after post-use
cleaning, may be stored dry but not sterile.

[0030]Aqueous diluents or vehicles used in large volume must be kept
sterile; once opened, concentrated additives may be kept clean, but not
necessarily sterile, with preservatives, as long as the quantities of
preservatives needed to prevent microbial overgrowth, like the quantities
of non-aqueous solvent needed to dissolve therapeutic doses of
non-aqueous drugs for two-phase liquid-liquid suspension, are
sufficiently small to be non-toxic and have no other adverse effects when
diluted for nebulization. "Other adverse effects" would include
impairment of nebulizer operation by sufficient concentrations of
quaternary ammonium disinfectants which act as detergents to reduce
surface tension, impair mist generation and thereby prolong treatment
time. Most non-aqueous solvents have antimicrobial properties of their
own, reducing the quantity of other preservatives needed for that
purpose.

[0031]The present invention also relates to a method for improving
delivery efficiency of any drug delivered via a jet nebulizer or other
nebulizer with a similar amount of dead space. Most present day jet
nebulizers stop generating aerosol when the volume remaining in the
chamber drops below approximately 1 ml. This is a significant fraction of
a 2.5 ml dose of most unit dose medications marked for use with these
devices. However, if the drug is packaged as a concentrate to be mixed
with an aqueous diluent for delivery, when the nebulizer stops delivering
aerosol and begins to sputter, indicating that the remaining volume has
dropped below the threshold for effective operation, another dose of
aqueous diluent can be added and nebulized into the patient, to wash in
the majority of the remaining medication. With presently available
nebulizers, volumes of 2.5 to 3.5 ml are optimal for this step. As will
be obvious to those of skill in the art upon reading this disclosure,
this method of minimizing drug wastage and improving drug delivery
efficiency is also useful with nebulizable formulations other than those
described herein.

[0032]The pharmaceutical industry is beginning to explore inhalation of
nebulized dosage forms as a route of systemic delivery of various drugs
for which there is not always effective and predictable oral absorption.
Some are water-soluble, others are not. The formulations and methods of
the present invention for drug delivery, as well as the methods for
minimizing drug wastage upon delivery of a nebulized drug, are clearly
applicable to delivery by nebulizer of such other drugs.

[0033]Dosing by mask to an infant or young child is effective but not
quantitatively reproducible, because of variable loss of nebulized drug
during expiration and variable deposition of each inspired "bolus"
because of variable depth of inspiration and duration of breath-holding.

[0034]However, dosing by mouthpiece to an older child or adult, with a
nebulizer chamber or compressor-chamber combination delivering a high and
reproducible fraction of respirable particles and with a low residual
volume at the end of aerosol generation, and a thumb valve to interrupt
mist generation and prevent drug loss during breath-holding and
expiration, is much more reproducibly quantitative. If drug is dosed into
the nebulizer chamber in a volume of 3.5 ml, and residual volume of the
nebulizer chamber is 0.5 or 1.0 ml (the lower value achievable with
certain models of nebulizer chamber), the fraction of drug left in the
nebulizer at the end of treatment will be 14.3 or 28.6%. Washing in this
left-over drug with 3 ml of sterile or buffered sterile saline in
accordance with the method described herein will reduce drug wastage to
2.4% or 9.5%. Accordingly, using the formulations and methods of the
present invention it is now feasible for developers of both respiratory
and non-respiratory drugs to quantitatively deliver drugs by inhalation
to older children and adults using economical and reliable nebulizer
systems that are already available.

[0035]The developer of a specific drug application has various options in
using the formulations and methods of this invention.

[0036]For example, in one embodiment, a water-insoluble drug can be mixed
with either a unit dose formulation of a water-soluble drug in aqueous
diluent prescribed for concurrent administration, or with a commercially
available sterile saline or buffered sterile saline diluent, with or
without addition of a concentrated, small volume of any other
water-soluble drug also prescribed for concurrent administration. In this
embodiment, it is preferred that any remaining drug or drugs in the
nebulizer chamber be washed in via an additional aliquot of commercially
available sterile saline or buffered sterile saline diluent.

[0037]In another embodiment, for a water-soluble drug, the drug can be
supplied as a concentrate for dilution with a commercially available
sterile saline or buffered sterile saline diluent, or as a pre-packaged
unit dose. In this embodiment, it is also preferred that any remaining
drug in the nebulizer chamber be washed in via an additional aliquot of
commercially available sterile saline or buffered sterile saline diluent.
This embodiment of the present invention is particularly useful for water
soluble drugs which are stable in physiologically compatible diluents for
the time needed for nebulization, but lack long term shelf-life stability
when stored under the same conditions. Instead, the drugs have long term
shelf-life stability when stored at high concentration in small volumes
of physiologically incompatible water-miscible diluents which can be made
pharmaceutically acceptable for nebulizer administration in accordance
with the present invention by dilution with appropriately formulated
diluents. Certain drugs, while water soluble, require alkaline or acidic
conditions or storage in non-aqueous but water-miscible vehicles to
maintain chemical stability over a reasonable shelf life. For example,
formoterol exhibits long term stability in glacial acetic acid, in which
unit doses could be stored at high concentration in very small volumes.
Aqueous solutions outside of the pH range from ˜4.5 to ˜9.5
are not pharmaceutically acceptable for nebulizer administration.
However, in accordance with the present invention, a drug stored in a
small volume of glacial acetic acid can be rendered pharmaceutically
acceptable for nebulization by mixing prior to nebulization with an
appropriately buffered diluent.

[0038]The present invention provides formulations for nebulizer
administration of water-soluble drugs which comprise a drug which is
soluble in a pharmaceutically acceptable nebulizer diluent but lacks
acceptable shelf-stability in such vehicles. In these formulations, the
drug is stored at high concentration in a small volume of a
pharmaceutically unacceptable vehicle in which it has acceptable
shelf-life stability, and mixed with a large volume of a diluent
appropriately formulated to render the resulting mixture pharmaceutically
acceptable for nebulization. Physiologically incompatible storage
conditions that can be neutralized by appropriately formulated buffers
include, but are not limited to, pH, the presence of various chemical and
biochemical stabilizing agents, enzyme inactivators and receptor blockers
which can be neutralized by either or both of dilution and/or physical
and/or chemical action. The large volume of aqueous diluent added to
produce the nebulizer formulation may also contain additional
water-soluble drugs to be delivered to a patient concurrently with
water-insoluble drug stored in the pharmaceutically unacceptable vehicle.

[0039]Commercially available formulations of sterile saline or buffered
sterile saline include: individually sealed 3 ml unit dose ampules with a
present cost to the user of approximately $0.30/ampule ($0.10 per ml); 8
ounce pressurized metered dose, multi-dose canisters of sterile saline
manufactured as a nebulizer diluting solution, dispensing 1 ml each time
it is pressed, at a cost of approximately $0.042 per ml; and 12 ounce
pressurized non-metered dose, multi-dose canisters of borate-buffered
sterile saline sold as a cleaning solution for contact lenses, which
ranges in cost from approximately $0.009 to $0.015 per ml.

[0040]A manufacturer of formulations of the present invention can achieve
the greatest reduction in combined insurer plus user cost, without
reducing its own revenues per dose sold, by obtaining FDA certification
of its drug for use with the least expensive formulation of sterile
saline or buffered sterile saline diluent. Currently, 12 ounce
pressurized non-metered dose, multi-dose canisters of buffered sterile
saline marketed as a cleaning solution for contact lenses are the least
expensive formulations. The manufacturer of a drug using this product as
a diluent can package each multi-dose bottle of concentrated solution of
drug with a quantitative measuring device and instructions for its use
with pressurized, non-metered-dose, multi-dose canisters of sterile
saline.

[0041]The design features of a quantitative measuring device useful in the
present invention can be best understood as features to implement the
following performance specification. The device shall quickly, accurately
and reproducibly measure and dispense into a nebulizer chamber a
pre-determined (i.e. not user adjustable) volume in the several
milliliter range of a physiologic saline or buffered saline solution that
has just been released from a pressurized canister. Since the saline will
contain effervescing bubbles of trapped propellant as it is dispensed
into the device, the device must accommodate the volume of bubbles and
allow them to dissipate without affecting the accuracy of the volume it
then dispenses.

[0042]Representative embodiments of a quantitative measuring device for
use in preparing formulations of the present invention are depicted in
FIGS. 1a, 1b and 1c and in FIGS. 2a, 2b and 2c. In simplest form, the
measuring device comprises a tubular body 1, preferably cylindrical in
shape as this geometry is easy to keep clean and is less favorable for
trapping of bubbles as compared to polygonal shapes. The bottom of the
tube 2 is closed and is preferably hemispherical in shape, again for ease
in cleaning and to prevent trapping of bubble in corners. The top of the
tube 5 is open. In one embodiment of the invention, the top of the tube 5
is tapered inward, in similar fashion to the top of a jar, to minimize
spills when the device is tapped to dislodge bubbles. In another
embodiment, the tubular body of the device 1 is minimally conical,
increasing in diameter from bottom to top by up to 1 to 2% per unit
length. This design should allow a less expensive fabrication process.
The reduced spill tendency achieved by a narrowed neck in the first
embodiment is achieved in this embodiment by increasing its length. The
following support designs or any other support shape that meets the
performance specifications described herein can be used in both of these
embodiments.

[0043]A support 4 is molded into the tubular body 1 to hold the tube at a
convenient angle to allow bubbles of propellant in the diluent to
effervesce without displacing volume to be measured from the tube. In one
embodiment, as depicted in FIGS. 1a, 1b, and 1c, the support 4 comprises
two pieces, 4a and 4b which form a trapezoidal rest 4a which supports the
tube at a selected angle, and a triangular brace 4b which provides
structural support for the rest. In another embodiment, as depicted in
FIGS. 2a, 2b and 2c, the support 4 comprises two triangular wings 4c and
a trapezoidal bridge 4d located between the wings for support. In both
embodiments, a proturbance 6 is placed on the outer surface of the
hemispherical bottom 2 of the tubular body 1. This proturbance 6 provides
a resting point for the device when placed on a flat surface at an angle
against the support. The tubular body 1 also comprises a square hole 3
with sides parallel and perpendicular to the long axis of the tubular
body 1 and centered on the side of the tube which is pointed up when the
device is rested on its support 4. The hole 3 is sized and positioned so
that when the device is filled with slightly more diluent than a desired
dose and positioned vertically, the level of diluent will be above the
bottom of the hole 3. In a preferred embodiment, the device further
comprises proturbances, 7a and 7b, on the outer surface at the top of the
tubular body, and proturbance 10 on the outer surface at the bottom of
the tubular body to facilitate gripping the device with the thumb below
proturbance 7a and the middle finger below proturbance 7b, to expel extra
diluent through the hole 3 by gentle tapping. The distance 8 from the
bottom 2 of the tubular body 1 to the bottom of the hole 3 is fixed so
that the device will deliver the desired volume of diluent when used as
described herein. The device may further comprise an optional fill line 9
on the outer surface of the tubular body 1 which provides a guide to
slightly overfill the tubular body 1 from a non-metered, dose-pressurized
canister, to allow for effervescence and subsequent delivery of an
accurate dose, with minimal wastage. The device may optionally further
comprise additional proturbances 11, located on the outer surface of the
tubular body 1 at the top 5 and bottom 2 which serve as finger grips to
grasp the device when rocking it on its support 4, to let it gently
bounce on proturbance 6 to dislodge any bubbles that may adhere to the
inner surface after completion of effervescence. Users may alternatively
press down on proturbance 7a to rock the device on its support and let it
fall back, to dislodge any bubbles.

[0044]To use this device, sterile saline or sterile buffered saline
diluent is dispensed into the device from the non-metered,
dose-pressurized canister in which it is supplied. The device is tipped
to its desired fill angle as it is filled, to keep its contents from
spilling out through hole 3. The device is filled to the fill line 9, and
placed on a flat surface to allow effervescing bubbles to rise to the
surface of the liquid in the device. Any bubbles that may have adhered to
the inner surface of the device can be dislodged by tilting the device
onto its support and letting it fall back, so that the proturbance 6
falls against the surface on which the device rests thereby jarring the
bubbles loose. The device is then picked up, held over the sink, rotated
to a vertical position, and proturbance 10 is gently tapped against the
inside wall of the sink to jostle diluent in excess of the desired fill
level out of hole 3. Proturbances 7a and 7b are incorporated into this
invention to reduce the risk of the device slipping out of the user's
hand, when it is tapped against the inner side wall of a sink to expel
excess liquid. The remaining content of the device is then poured into
the nebulizer chamber, either before or after other medications are added
or as a chaser after the nebulizer has stopped generating mist.

[0045]If the geometry of a nebulizer is such that the support of the
measuring device gets in the way of pouring from the measuring device
into the chamber, the diluent may first be poured into a medicine cup and
then into the nebulizer chamber. Accordingly, a manufacturer wishing to
minimize the possibility of having the protruding support of the diluent
dose-measuring device interfere with pouring into certain models of
nebulizer chambers may also supply a small plastic medicine cup together
with the device, with a multi-dose bottle of the drug.

[0046]The measuring device of the present invention is designed so that
the volume of diluent or chaser in the measuring device, which is then
poured into the receptacle, is accurate and reproducible, independent of
the initial volume of overfill and independent of tapping pressure and
technique.

[0047]The manufacturer of drugs for nebulizer formulation which are
provided in multi-dose bottles containing a concentrated solution of drug
can also include a dosing device to facilitate the clean, inexpensive and
accurate measurement and dosing of small volumes of concentrated drug
solution from the multi-dose bottle, into the nebulizer chamber for
mixing with large volumes of aqueous media to form the two-phase
liquid-liquid suspension. The performance specification for this device
is that it be able to accurately measure and dispense volumes from 0.05
to 0.5 ml, drawn from a multi-dose bottle, that is be as easy to keep
clean as the graduated plastic dropper tips presently supplied with
concentrated aqueous multi-dose nebulizer formulations for which dose
volumes range from 0.25 to 0.5 ml, and that it be inexpensive to
manufacture and distribute. The same device may be used for accurate
dosing of similarly small volumes of water soluble drugs in aqueous
media, extending downward from about 0.25 ml to 0.05 ml the range of
clean, inexpensive and accurate measurement of small volumes of all drugs
for nebulizer administration.

[0048]This device of the present invention comprises a screw-on cap for a
multi-dose medicine bottle, either incorporating a gasket or with an open
top and holding in place a gasket with a flexible seal, impermeable to
its liquid contents and preferably transparent, to fit around the shaft
of a mass-produced, plastic 0.5 ml medicine syringe so that the syringe
can slide in and out of the bottle. The syringe is similar to those
manufactured for individuals with diabetes to self-inject insulin, except
that for this use it will be provided either with no needle or with a
relatively large bore, blunt tip needle.

[0049]The device, as depicted in FIG. 3, comprises the components and
elements described above. Namely, this device comprises a screw-on cap
11, a gasket 12 fitted into the top of the screw-on cap; and a liquid
tight seal 13 which fits around the shaft of a plastic syringe, allowing
the syringe to slide in and out of the bottle. It combines the
cleanliness in repeated use of an ordinary medicine dropper top, which
need never be put down anywhere but inside its clean bottle, the accuracy
of a syringe, and the economy of using a product that is already mass
produced for a very large market.

[0050]Different plastic syringes may be made with silicone lubricants of
different composition, or with no lubricant at all. In selecting a
syringe for this use with non-aqueous media, a drug manufacturer will
have to ensure that syringe lubricant is not dissolved by the non-aqueous
medium employed, making the syringe stick and exposing the patient to
inhalation of lubricant.

EXAMPLE

[0051]A solution of flunisolide dissolved in a mixture of propylene and
polyethylene glycol is marketed for topical use as a nose spray in
allergic rhinitis. This solution may be administered by nebulizer as the
small volume, non-aqueous phase of what behaves as a two-phase
liquid-liquid suspension in aqueous media, as described herein.

[0052]This formulation of flunisolide has been demonstrated to offer young
children the benefit of effective nebulized topical steroid therapy for
asthma for the first time. In doses of 50 to 100 μg given up to 4
times per day, this formulation has proven convenient, effective and free
of apparent adverse effects in the treatment of multiple patients, many
over relatively long term treatment intervals. Both physician and parents
have observed improved control of asthma, reduced need for acute care,
reduced need for oral steroids, and reduced need for hospital and
emergency department care in more than one hundred patients treated with
this formulation of the present invention.

[0053]For these patients, a measured volume, typically 0.25 to 0.5 ml, of
flunisolide dissolved in a mixed glycol non-aqueous phase was mixed with
2.5 to 3.5 ml of aqueous phase consisting of a physiologic or buffered
physiologic saline solution or a unit dose formulation of a
co-administered water-soluble drug in aqueous solution, with or without
other water-soluble drugs added as measured volumes of multi-dose aqueous
formulations.

[0054]When the nebulizer began to sputter, indicating insufficient
remaining volume for effective aerosol generation, the parent or patient
was instructed to add an additional 2.5 to 3.5 ml of sterile saline or
sterile buffered saline, from a pressurized, multi-dose container.

[0055]Patients in the treatment group reported in this example generally
had insurance coverage for medications, but had to purchase diluent
out-of-pocket. With an average treatment frequency for the more than 100
patients of two treatments per day for an average treatment interval
greater than one year, the availability of sterile buffered saline
diluent at a cost of approximately $0.01 per ml, dosed with a slightly
less precise measuring device than that described herein, was a major
enhancer of compliance with prescribed treatment.